Seminars in Cancer Biology xxx (xxxx) xxx–xxx

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Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Ginger and its active compounds in cancer therapy: From folk uses to nano-
therapeutic applications
M.F. Mahomoodallya, M.Z. Aumeeruddya, Kannan R.R. Rengasamyb,⁎, S. Roshanc, S. Hammadd,e,
J. Pandoheea,f, Xuebo Hug, G. Zenginh
a
Department of Health Sciences, Faculty of Science, University of Mauritius, 230 Réduit, Mauritius
b
Department of Bioresources and Food Science, College of Life Sciences, Konkuk University, Seoul 05029, South Korea
c
Deccan School of Pharmacy, Darussalam, Aghapura, Hyderabad, 500001, Telangana, India
d
School of Pharmacy, Monash University, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia
e
Institute of Pharmaceutical Sciences (IPS), University of Veterinary & Animal Sciences (UVAS), Lahore, Pakistan
f
Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Joondalup, WA 6027, Australia
g
College of Plant Sciences and Technology, Huazhong Agricultural University, Wuhan, China
h
Department of Biology, Faculty of Science, Selcuk University, Turkey

ARTICLE INFO ABSTRACT

Keywords: Ginger is a spice that is renowned for its characteristic aromatic fragrance and pungent taste, with documented
Zingiber officinale healing properties. Field studies conducted in several Asian and African countries revealed that ginger is used
Microbiome traditionally in the management of cancer. The scientific community has probed into the biological validation of
Gingerol its extracts and isolated compounds including the gingerols, shogaols, zingiberene, and zingerone, through in-
Shogaol
vitro and in-vivo studies. Nonetheless, an updated compilation of these data together with a deep mechanistic
Enzyme inhibition
Combination therapy
approach is yet to be provided. Accordingly, this review highlights the mechanisms and therapeutics of ginger
Nanoformulation and its bioactive compounds focused on a cancer context and these evidence are based on the (i) cytotoxic effect
against cancer cell lines, (ii) enzyme inhibitory action, (iii) combination therapy with chemotherapeutic and
phenolic compounds, (iv) possible links to the microbiome and (v) the use of nano-formulations of ginger
bioactive compounds as a more effective drug delivery strategy in cancer therapy.

1. Introduction
The ginger plant is a herbaceous flowering plant that belongs to the
Zingiberaceae family. Scientifically named as Zingiber officinale Roscoe,
the perennial plant consists of a pseudo-stem, yellow flowers and tu-
berous rhizomes, which are also known as ginger root or commonly
called ginger. It is the rhizomes of ginger plants that are the most
sought-after portion due to its aromatic odour and pungent taste.
Ginger is therefore an important ingredient for culinary purposes.
Originally from Asia, the most common custom usage of ginger was as a
flavouring agent in its various form and this could include fresh, dried,
pickled, powdered and preserved and, more interestingly, as a tonic
root to treat many ailments for its medicinal benefits. Nowadays, the
plant is grown on a large scale across the world in tropical regions, such
as the West Indies, Africa and India, for its consumption as a spice,
dietary supplement [1].
As a natural product, ginger is a complex spice composed of
carbohydrates, water, protein, lipids, fibres and volatile essential oils
[2,3]. Using advanced mass spectrometry-based identifications, che-
mical analysis of the essential oil reveals that the root contains hun-
dreds of different compounds [4,5]. The majority of compounds iden-
tified in ginger are from the chemical classes gingerols, shogaols,
zigiberenes and zingerone (chemical structures shown in Fig. 1). To a
lesser extent, terpene components such as bisabolene, farnesene, ses-
quiphellandrene, curcumene and phytosterols, vitamins and minerals
can also be found in specific varieties of ginger. Thus, the nutraceutical
value of ginger is attributed to its complexity of bioactive compounds
especially the major phenolic classes such as the gingerols, shogaols,
zingiberene, paradol, and zingerone [6].
Gingerols (23–25%) are part of the phenolic compound class and
these volatile organic compounds are known to account for the strong
taste of fresh Zingiber officinale. 6-gingerol is the main compound ac-
countable for the pungency of the rhizome, while the other gingerols
(4-, 8-, 10- and 12-gingerol) are present in lower amounts (1–10%).

⁎
Corresponding author.
E-mail address: Rengasamy@enzymeinhibitors.co.in (K.R.R. Rengasamy).

https://doi.org/10.1016/j.semcancer.2019.08.009
Received 3 July 2019; Received in revised form 26 July 2019; Accepted 9 August 2019
1044-579X/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: M.F. Mahomoodally, et al., Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2019.08.009
M.F. Mahomoodally, et al. Seminars in Cancer Biology xxx (xxxx) xxx–xxx

Fig. 1. The chemical structures of gingerol, shogal, gingerdione and zingerol.

Fig. 2. Cytotoxic mechanisms of action of two studied compounds in Ginger.

However, being thermally labile, these compounds are converted to
shogaols at high temperatures, for example while cooking, and gives
ginger its spicy-sweet aroma. The biological properties of gingerols and
shogaols are recognized to possess antimicrobial, anticancer, anti-
oxidant, anti-inflammatory, and anti-allergic propensities [7,8]. Sho-
gaols are known to have anti-coughing effects, gingerol on the other
hand accounts for the analgesic properties of ginger. In addition to the
phenolics, diarylheptanoids and zingerone have also been identified in
ginger and are believed to be bioactive compounds contributing to
health benefits [5,6,9].
Using ginger in the treatment of cancer is not a new concept, it has
been a customary practice in the folk medicine throughout the world
and has been showed to be effective by several field studies. In India,
the juice and decoction of the rhizome is taken orally [10,11]. In Sin-
gapore, the cooked rhizome is used as a mean for cancer prevention
[12]. An infusion of the rhizome is used against breast cancer by the
Palestinians [13]. In addition, as a general cancer treatment, a decoc-
tion of the root is prepared from a mix of ginger root, turmeric, and
honey, and two doses are ingested on a daily basis. A concoction can
also be made from a mix of ginger root, nigella, and camel milk, and

2
M.F. Mahomoodally, et al.
one glass is taken daily before breakfast [14]. Another recipe used by
the Palestinians to manage stomach and liver cancer uses 100 g of the
ground dried rhizomes boiled in water and given twice daily after meals
[13]. In Morocco, ginger root is ground with honey and taken orally
[15]. Another traditional use of ginger is as a paste; in Ghana the root/
rhizome is ground and the resulting mixture is either orally consumed
or used as a massage remedy for stomach and brain cancer [16].
Recently, pharmacological studies have probed into the validation
of such claims, and now, ginger together with its associated bioactive
compounds have been proven to have potential anticancer properties.
In this context, this review aims at highlighting the cytotoxic effect of
ginger and its compounds against various types of cancer, focusing on
its enzyme inhibitory mechanism, combination therapy with other
agents and the potential of nano-formulations of ginger bioactive
compounds as a novel beneficial in cancer treatment.
2. Overview of anti-cancer properties of ginger
There has been an increasing amount of studies showing promising
results on the cytotoxic effect of ginger extracts and its bioactive
compounds against several cancer cells including breast, cervical, col-
orectal, leukemia, liver, lung, nasopharyngeal, ovarian, prostate, and
retinoblastoma (see detailed findings and mechanisms in Table 1 and
Fig. 2).
2.1. Breast cancer
Ansari et al [17] showed that the methanolic solution of ginger
displayed a time-dependent cytotoxic effect on the breast cancer cell
line (MDA-MB-231), with IC50 of 86.7 and 57.5 μg/mL after 24 and 48 h
incubation, respectively. In addition, the two derivatives of 6-oxo-
shogaol isolated from ginger, namely Z-6-oxo-6-shogaol and Z-6-oxo-8-
shogaol, showed potent cytotoxic action on MCF-7 cell, with IC50 of
6.27 and 47.22 μM, respectively, after 48 h exposure [5]. 6-shogaol was
found to hinder the growth of cancer cell (breast & colon) by activating
the peroxisomal proliferator activated receptor γ (PPARγ) [18]. It has
been observed [19] that 10-gingerol caused a considerable upsurge in
the initiation of caspase-3 and inhibited orthotopic tumour growth of
spontaneous breast cancer metastasis. More pertinently, the authors
reported that 10-gingerol inhibit metastasis to multiple organs (in-
cluding lung, bone, and brain).
2.2. Cervical cancer
A study by Liu et al [20] found that 6-shogaol exhibited high in-
hibition (IC50 = 14.75 μM) against HeLa cells, which was more effec-
tive compared to α-zingiberene (IC50 = 60.6 μg/mL), 6-gingerol
(IC50 = 96.32 μM), and [10]-gingerol (IC50 = 52.4 μM) [21–23]. The
essential oil was also found to be cytotoxic to SiHa cells, showing IC50
value of 38.6 μg/mL, more effective than α-zingiberene
(IC50 = 46.2 μg/mL) [21]. 6-gingerol blocked the cell cycle in G0/G1-
phase in HeLa cell and eventually caused cells death. The compound
reduced cyclin (A, D1, E1) expression, slightly decreased CDK-1, p21,
and p27 while cyclin B1 and E1 protein were unaffected. Western blot
analysis also indicated the pathway of apoptotic activation, with an
increased Bax/Bcl-2 ratio, cytochrome c release, cleavage of caspase-3,
-8, -9 and phosphoribosyl pyrophosphate (PRPP) in challenged cells.
Consequently, 6-gingerol triggered AMP-activated protein kinase
(AMPK), and inhibited PI3K/AKT phosphorylation, thus leading to a
decrease in P70S6K expression and ultimately inhibited mTOR [23].
2.3. Prostate cancer
Ginger and its active compounds were also found to reduce the cell
viability of a number of prostate cancer cells including DU145, LNCaP,
C4-2, C4-2B, and PC-3. 10-gingerol (IC50 = 59.7 μM) was more
3
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
cytotoxic than 6-shogaol (IC50 = 100.0 μM) against PC-3 cell [22]. In
addition, at a concentration of 40 μmol/L, 6-shogaol abridged the sur-
vival of DU145, LNCaP, and PC-3 by 80%, 96%, and 76%, respectively,
after 72 h exposure [24]. The authors also found that 6-shogaol in-
hibited STAT3 and NF-kB signaling, decreased interleukin (IL)-6-in-
duced STAT3 initiation and also inhibited TNF-α-induced NF-kB ac-
tivity. Moreover, 6-shogaol decreased the level of numerous STAT3 and
NF-kB-regulated target genes at the proteinomic stage, such as cyclin
D1, survivin, and cMyc. 6-shogaol also modulated the mRNA levels of
several chemokine, cytokine, cell cycle, and apoptosis regulatory genes
including IL-7, CCL5, BAX, BCL2, p21, and p27. 6-gingerol also induced
dose- and time-dependent apoptosis in LNCaP human prostate cancer
cells mainly via caspase-3 expression with the resulting degradation of
PARP [25].
2.4. Lung cancer
The cytotoxic effect of 6-gingerol (IC50 = 136.73 μM after 24 h ex-
posure) on H-1299 lung cancer cell was proved by Lv et al [26]. Peng
et al [22] found that 6-shogaol (IC50 = 22.9 μM) was more effective
than 10-gingerol (IC50 = 85.4 μM) against A549 lung cancer cell. When
evaluated against human lung cancer cells, 6-shogaol was also observed
to initiate autophagy via the inhibition of AKT/mTOR pathway [27].
2.5. Liver cancer
Ginger extract was observed to diminish the raised activity of NFκB
and TNF-α in rats with liver cancer [28]. In addition, other ginger
derivatives such as Z-6-oxo-6-shogaol, Z-6-oxo-8-shogaol and E-4-iso-
shogaol, exhibited cytotoxic effect against HepG2 cell, with IC50 scores
of 8.92 μM, 45.14 μM, 14.87 μM, respectively [5], which was more
effective than the essential oil (IC50 = 635.1 μg/mL) [29]. 72 h ex-
posure of 6-shogaol also showed higher cytotoxic effect on BEL-7404
compared to 10-gingerol [22]·
2.6. Blood cancer
6-shogaol was a more effective cytotoxic agent against HL-60 and
K562 leukemic cell (supported by IC50 values of 7.9 μM and 24.2 μM,
respectively), which was more effective compared to 10-gingerol [22].
Also, Liu et al [30] observed that 6-shogaol specifically stimulated
apoptosis in transformed and primary cellular leukemia. Data from
immunoblotting studies revealed that 6-shogaol caused apoptosis by a
process which involves eIF2α dephosphorylation and caspase activa-
tion-dependent breakdown of eIF2α.
2.7. Colorectal cancer
A plethora of supporting information that ginger and its bioactive
derivatives are cytotoxic to several colon cancer cell lines with HCT15,
HCT116, SW480, LoVo, and HT29 cells (see Table 1). It has been [31]
observed that 6-gingerol caused apoptosis in colorectal cancer cells by
upregulating NAG-1 and G1 cell cycle arrest via the down-regulation of
cyclin D1. Several mechanisms seem to be responsible for the action of
6-gingerol, including protein degradation along with β-catenin, PKCε,
and GSK-3β pathways. 6-gingerol also stimulated caspase-dependent
apoptosis and prevented phorbol myristate acetate-induced prolifera-
tion in colon cancer cells through the inhibition of MAPK/AP-1 sig-
naling. On top of that, using p53(-/-) and p53(+/+) HCT-116 color-
ectal cancer cells, the researchers confirmed that p53/p21 was the
principal pathway contributing to the G2/M cell cycle arrest induced by
6-shogaol [32]. It was [33] found that 6-shogaol induced-apoptosis
primarily via the pathway involving the mitochondria, and the Bcl-2
family might play as a central regulator.
M.F. Mahomoodally, et al. Seminars in Cancer Biology xxx (xxxx) xxx–xxx

Table 1
Cytotoxicity of ginger and bioactive compounds against cancer cell lines.
Cancer type Cell line Extract type/compound Incubation time Findings References

Breast MDA-MB-231 Methanol extract 24 h and 48 h 24 h: IC50 = 86.7 μg/mL [17]

48 h: IC50 = 57.5 μg/mL
Ethyl acetate fraction 24 h At 100 μg/mL, reduced the cell viability by 44% [43]
obtained from crude
methanolic extract
MCF-7 Ethyl acetate fraction 24 h At 100 μg/mL, reduced the cell viability by 36% [43]
obtained from crude
methanolic extract
Essential oil 24 h IC50 = 82.6 μg/mL [21]
(Z)-6-oxo- [6]-shogaol 48 h IC50 = 6.27 μM [5]
(Z)-6-oxo- [8]-shogaol 48 h IC50 = 47.22 μM [5]
α-zingiberene 24 h IC50 = 172.0 μg/mL [21]
Cervical HeLa Chloroform extract 48 h IC50 = 74.32 μg/mL [44]
Ethanol extract 48 h IC50 = 33.78 μg/mL [44]
Essential oil 24 h MTT assay; IC50 = 141.4 μg/mL [29]
NRU assay; IC50 = 129.9 μg/mL
24 h IC50 = 46.0 μg/mL [21]
Methanol extract 24 h and 48 h 24 h: IC50 = 46.5 μg/mL [17]
48 h: IC50 = 37.5 μg/mL
6-shogaol 24 h IC50 = 14.75 μM [20]
72 h IC50 = 62.5 μM [22]
α-zingiberene 24 h IC50 = 60.6 μg/mL [21]
6-gingerol 48 h IC50 = 96.32 μM [23]
[10]-gingerol 72 h IC50 = 52.4 μM [22]
SiHa α-zingiberene 24 h IC50 = 46.2 μg/mL [21]
Essential oil 24 h IC50 = 38.6 μg/mL
Colorectal HCT15 6-Gingerol 24 h IC50 = 100 μM [45]
HCT-116 6-Gingerol 24 h IC50 = 160.42 μM [26]
Ethyl acetate fraction 24 h and 48 h Reduced the viability by 79 % and 88% at 200 μg/mL at 24 h and [43]
obtained from crude 48 h, respectively
methanolic extract
Ethanol extract 24 h IC50 = 496 μg/mL [46]
[6]-Gingerol 48 h,72 h or 96 Dose- and and time-dependent cytotoxic effect, with an IC50 value of [32]
h 283 μM
SW480 Ethyl acetate fraction 24 h and 48 h Reduced the viability by 55 % and 76% at 200 μg/mL at 24 h and [43]
obtained from crude 48 h, respectively
methanolic extract
[10]-Gingerol 24 h With 50-100 μM, [10]-gingerol reduced the cell viability in a [47]
concentration-dependent manner
[6]-Gingerol 48 h,72 h or 96 Dose- and and time-dependent cytotoxic effect, with an IC50 value of [32]
h 205 μM
LoVo Ethyl acetate fraction 24 h and 48 h Reduced the viability by 59 % and 80% at 200 μg/mL at 24 h and [43]
obtained from crude 48 h, respectively
methanolic extract
HT 29 Ethanol extract 24 h IC50 = 455 μg/mL [46]
Mucus-secreting Essential oil 24 h IC50 = 40 μL/mL [48]
HT29
Non-mucus- Essential oil 24 h IC50 = 60 μL/mL [48]
secreting HT-29
Leukemia Raw 264.7 cell 6-Gingerol 24 h IC50 = 102 μM [45]
HL-60 α-zingiberene 24 h IC50 = 80.3 μg/mL [21]
Essential oil 24 h IC50 = 39.1 μg/mL [21]
6-shogaol 72 h IC50 = 7.9 μM [22]
[10]-gingerol 72 h IC50 = 75.4 μM [22]
K562 6-shogaol 72 h IC50 = 24.2 μM [22]
[10]-gingerol 72 h IC50 = 112.5 μM [22]
Liver HepG2 Essential oil 24 h IC50 = 635.1 μg/mL [29]
Ethyl acetate fraction 24 h At 100 μg/mL, reduced the cell viability by 30% [43]
obtained from crude
methanolic extract
(Z)-6-oxo- [6]-shogaol 48 h IC50 = 8.92 μM [5]
(Z)-6-oxo- [8]-shogaol 48 h IC50 = 45.14 μM [5]
(E)- [4]-isoshogaol 48 h IC50 = 14.87 μM [5]
BEL-7404 6-shogaol 72 h IC50 = 11.8 μM [22]
[10]-gingerol 72 h IC50 = 95.2 μM [22]
Lung H-1299 6-gingerol 24 h IC50 = 136.73 μM [26]
A549 6-shogaol 72 h IC50 = 22.9 μM [22]
[10]-gingerol 72 h IC50 = 85.4 μM [22]
Murine fibrosarcoma L929 Essential oil 3h IC50 = 41 μg/mL [49]
Chloroform extract 48 h IC50 = 87.28 μg/mL [44]
Ethanol extract 48 h IC50 = 101.0 μg/mL [44]
6-Gingerol 24 h IC50 = 102 μM [45]
Nasopharyngeal CNE 6-shogaol 72 h IC50 = 43.8 μM [22]
[10]-gingerol 72 h IC50 = 88.1 μM [22]
(continued on next page)

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Table 1 (continued)

Cancer type Cell line Extract type/compound Incubation time Findings References

Ovarian SKOV-3 Extract (Sigma-Aldrich: 24 h, 48 h and IC50 was 97 μg/mL, 60 μg/mL and 40 μg/mL at 24 h, 48 h and 72 h, [50]
W252108) 72 h respectively
Prostate DU145 Methanolic fraction 24 h IC50 = 45.3 μg/mL [51]
Methanol extract 72 h IC50 = 95 μg/mL [52]
6-Shogaol 24 h, 48 h, and Reduced in % survival of cells, at a concentration of 40 mmol/L, was [24]
72 h 64%, 80%, and 80% after 24 h, 48 h, and 72 h, respectively
LNCaP Methanol extract 72 h IC50 = 75 μg/mL [52]
6-Shogaol 24 h, 48 h, and Reduced in % survival of cells, at a concentration of 40 mmol/L, was [24]
72 h 67%, 85%, and 96% after 24 h, 48 h, and 72 h, respectively
C4-2 Methanol extract 72 h IC50 = 512 μg/mL [52]
C4-2B Methanol extract 72 h IC50 = 240 μg/mL [52]
PC-3 Methanol extract 72 h IC50 = 250 μg/mL [52]
6-Shogaol 24 h, 48 h, and Reduced in % survival of cells, at a concentration of 40 mmol/L, was [24]
72 h 66%, 78%, and 76% after 24 h, 48 h, and 72 h, respectively
72 h IC50 = 100.0 μM [22]
[10]-gingerol 72 h IC50 = 59.7 μM [22]
Retinoblastoma RB355 Gingerol 12 h, 48 h, and Showed a concentration-dependent as well as time-dependent growth [53]
72 h inhibition. A 250-μM dose of gingerol led to 82.7%, 83.1%, and 85.2%
growth inhibition at 12-h, 48-h, and 72-h incubations

3. Links to the microbiome
With the increasing evidence that ginger has beneficial effects on
colorectal and intestinal cancer, the search to demystify the links and
relationship between the bioactive compounds present in ginger and
the microbiome is becoming more and more critical. The microbiome is
the set of microorganisms that live inside a system; the human body
itself is home to 10–100 trillion symbiotic microbial cells, most of
which live in the human gut alone [34]. It estimated that the total
amount of bacterial cells living in a human significantly outnumber
human cells and that microbes in the human intestines play a vital role
in maintaining a healthy gut function. Some of these functional con-
tributions include harvesting essential nutrients from non-digestible
food such as fibres [35], vitamin synthesis [36] and the immune system
[37]. The core human microbiome is in constant interaction with its
host and is susceptible to changes in various factors such as the host
lifestyle, diet, genotype, physiology, environment and disease status. In
other words, the microbiome and its human host are in a symbiotic
relationship where microbes have access to food components and ha-
bitable gut environment while simultaneously providing humans ben-
eficial by-product metabolites. A disbalance in this relationship has
been shown to lead to inflammatory bowel disease and colorectal
cancer. Diet therefore plays an essential role in establishing overall
health.
The various ways ginger can be employed to prevent/manage/ and/
or treat gastrointestinal cancer has been reviewed in many occasions
[36–40]. Most recently, Ganaie et al [41] investigated the chemo-pre-
ventive efficacy of zingerone on colon carcinogenesis in Wistar rats. The
four groups of rodents were given normal saline (control), 1,2-di-
methylhydrazine (dose rate used was 20 mg/kg), zingerone (dose rate
20 mg/kg) and zingerone again (dose rate 100 mg/kg). Key findings
were the decreased activity of cytochrome P4502E1 and decreased ROS
level with the ingestion of zingerone meaning that supplementation of
zingerone has the capability to be used as a chemopreventive agent.
Ganaie et al [41] also discussed the potential of zingerone to regulate
action of xenobiotic enzymes of Phase I cytochrome P4502E1 and its
ability to suppressed NF-kB-p65, COX-2, iNOS and PCNA, Ki-67.
Similarly, Wang et al [42] found that the gut microbiome has an
essential function in the metabolic pathway of 6-shogaol by reducing
the double bond and ketone group. They showed that 6-shogaol and its
metabolites interacts with the human gut microbiota and in mice mi-
crobiota through various chemical reactions in the intestines. As a re-
sult, the products of the chemicals processes adds to the anti-in-
flammation characteristics of ginger which are key in its anti-cancerous
activities with many studies linking ginger to inhibition of free radical
damage, which is the cause of many cancers, and especially in its po-
tential to control signaling molecules such as NF-κB, STAT3, MAPK,
PI3K, ERK1/2, Akt, TNF-α, COX-2, cyclin D1, cdk, MMP-9, surviving,
cIAP-1, XIAP and Bcl-2.
4. Enzyme inhibition
A number of enzymes are presently targeted as biomarkers in the
diagnosis or treatment of cancer. Targeting cellular metabolism asso-
ciated enzymes linked to cancer progression is considered to offer much
promise but remains a largely unexplored topic [54]·
4.1. Cytochrome P450
Cytochrome 450, shortened to CYP450, comprises a collection of
enzymes whose main function is the oxidative catalysis of numerous
endogenous and exogenous constituents. Such enzymes are involved in
the phase I metabolism of 80% of commonly used drugs, including
anticancer molecules, and therefore, CYP450 inhibitors are presently
being investigated to improve the pharmacokinetics of several antic-
ancer drugs [55].
Langhammer and Nilsen [56] found that ginger extracts obtained
from commercially available ginger capsule inhibited CYP activities
such as CYP1A2, CYP2D6, CYP3A4, with IC50 scores of 320, 445, and
565 μg/mL, respectively. In addition, it was [57] observed that 6-, 8-,
and 10-gingerol blocked the action of CYP450 activity. The three gin-
gerols exhibited potent inhibition on CYP2C9 activity, modest inhibi-
tion on CYP2C19 and CYP3A4, and weakly inhibited CYP2D6. Among
them, 8-gingerol showed the highest inhibition of P450 enzymes dis-
playing IC50 values of 6.8, 12.5, 8.7, and 42.7 μmol/L against CYP2C9,
CYP2C19, CYP3A4, and CYP2D6, respectively. Another study by
Mukkavilli et al [58] also found that 6-, 8-, and 10-gingerol, and 6-
shogaol repressed the main membrane-bound players of the CYP450
enzyme system, including CYP1A2, CYP2A6, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, and CYP3A enzymes.
4.2. Cyclooxygenase (COX)
Cyclooxygenase enzymes (specifically COX-2) are key molecular
targets for cancer intervention at both early and late stages. COX-2 is
over-expressed during carcinogenesis, and seems to be involved in the
start and progression of tumor [59]. 10- gingerol, 8-shogaol, and 10-
shogaol were found to hinder COX-2 with IC50 scores of 32, 17.5 and
7.5 μM, respectively [60]. In another study by Tjendraputra et al [61],
they observed that 10-gingerol, 6-shogaol, and 8-paradol exhibited

5
M.F. Mahomoodally, et al.
potent COX-2 inhibition with IC50 values of 3.7, 2.1, 3.4 μM, respec-
tively. In addition, 8-gingerdiol (IC50 = 12.5 μM), 8- gingerol
(IC50 = 10 μM), and its positional isomer (IC50 = 15.8 μM) displayed
comparatively strong COX-2 inhibitory activity.
4.3. Matrix metalloproteinases
Matrix metalloproteinases (MMPs) is a family of structurally related
zinc dependent endopeptidases which are key players for extracellular
matrix degradation, hence, are associated with the invasion and me-
tastasis of tumor. So far, more than 20 human MMPs have been ac-
knowledged, among which, MMP-2 and -9 are thought to be most sig-
nificant in tumor invasion due to their role in the degradation of type IV
collagen. Currently, agents reducing the expression of either MMP-2 or
MMP-9 have been found to effectively inhibit cancer cell invasion [62].
Interestingly, 6-shogaol was found to dose-dependently decrease MMP-
9 gene activation, protein expression and secretion by blocking nuclear
factor-kB activation [62]. Zingerone also displayed strong anti-angio-
genic activity by inhibiting MMP-2 and MMP-9 during tumor progres-
sion [63].
Moreover, Weng et al [64] observed that treatment of HepG2 and
Hep3B cells with 6-shogaol (1, 2.5, 5, and 10 μM) or 6-gingerol (5, 10,
25, and 50 μM), respectively, suppressed MMP-9 activity in a dose-de-
pendent manner while the activity of MMP-2 was not significantly
changed. Upon treatment of HepG2 cells for 24 h with 0–10 μM 6-
shogaol or 0–50 μM 6-gingerol, the mRNA expression of MMP9 was
nearly unchanged, except for 1 μM 6-shogaol treatment which caused a
dramatic reduction in the levels of MMP-9 mRNA. On the other hand,
24 h treatment of 6-shogaol or 6-gingerol in Hep3B cells reduced the
mRNA expression of MMP-9. Nonetheless, a decrease in MMP-9 mRNA
level was only observed after treatment with 6-gingerol.
Additionally, it was found that 6-gingerol treatment reduced MMP-2
and MMP-9 activities in MDA-MB-231 cells [65]. Also, 6-gingerol, at
levels above 5 μM, was able to reduce the quantity of MMP-2 protein in
the culture supernatant, but the level of MMP-9 protein remained un-
changed. However, 6-gingerol reduced the mRNA expression of both
MMP-2 and MMP-9.
4.4. Telemerase
Telomerase is another key target in cancer therapy. Without telo-
merase, the length of telomeres of typical somatic cells are reduced at
every cell division. When a telomere is shortened to a critical length at
the cellular level, that cell is prompted to cellular senescence.
Therefore, cellular senescence induced by telomere reduction is re-
garded as a tumor suppressor mechanism. However, more than 85% of
all cancers are able of maintaining the length of their telomeres by
reactivating telomerase to prevent cancer cells from the replicative
senescence [66,67].
Navakoon et al [66] showed that long-term incubation with sub-
cytotoxic concentration of ginger extract (ethyl acetate fraction), which
allowed A549 cells to multiply normally, stimulated telomere reduction
which subsequently induced cellular senescence in these cells, de-
monstrated by an upsurge in the senescence associated β‑galactosidase
positive cells and a decrease in clonogenicity.
The transcriptional regulation of telomerase reverse transcriptase in
human (hTERT) also tend to be a major mechanism towards controlling
the activity of telomerase. c-Myc is one transcription factor, which, col-
lectively with Max, binds to the E-box on the hTERT promoter, thereby
activating hTERT expression [67]. Tuntiwechapikul et al [67] observed
that ginger extract (ethyl acetate) can time- and concentration-depen-
dently inhibit the activity of the two main molecular targets of cancer,
hTERT and c-Myc, in A549 lung cancer cells. The cancer cells displayed
reduced telomerase activity due to decreased protein manufacture rather
than direct down regulation of telomerase. The decrease of hTERT ex-
pression tends to concur with the decrease of c-Myc activity.
6
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
4.5. Leukotriene A4 hydrolase
The proinflammatory enzyme, leukotriene A4 hydrolase (LTA4H), is
involved in the biosynthesis of leukotriene B4 (LTB4), a chemo-at-
tractant which causes an intense inflammatory reaction associated with
cancer development. LTA4H is reported to be highly expressed in col-
orectal carcinoma.
El-Naggar et al [68] found that methyl shogaol and 4′-O-prenyl- [6]-
gingerol displayed high LTA4H aminopeptidase (IC50 = 4.92 and
3.01 μM, respectively) and epoxide hydrolase inhibitory activities
(IC50 = 11.27 & 7.25 μM, respectively). Among the tested gingerols, 10-
gingerol was the most efficient inhibitor of LTA4H aminopeptidase
(IC50 = 21.59 μM) and epoxide hydrolase (IC50 = 15.24 μM). These
results corroborates with the observed in vitro cytotoxic effect of ginger
and isolated bioactive phytochemicals against colorectal cancer cells, as
mentioned above, which indicates their potential as natural inhibitors
of aminopeptidase and epoxide hydrolase for colorectal cancer.
5. Combinational therapy
The combination of two or more types of treatment to specifically
target cancer-inducing or cell sustaining pathways has become a fun-
damental of cancer therapy. This approach can potentially act in a sy-
nergistic and/or additive way and decreases drug resistance and toxi-
city [69].
In the study of Brahmbhatt et al [70], numerous binary blends of
ginger biophenolics were tested at several concentrations against the
human prostate cancer PC-3 cells. They found that cell proliferation
could be hindered by binary combinations of ginger bioactives. 83% of
gingerol combinations (6-gingerol+8-gingerol, 8-gingerol+10-gin-
gerol, 6-gingerol+10-gingerol) inhibited PC-3 proliferation in a sy-
nergistic manner. Another example is the grouping gingerol (90%) and
6-shogaol (6-shogaol+6-gingerol, 6-shogaol+8-gingerol, and 6-sho-
gaol+10-gingerol) displayed synergism. Very strong synergism was
exhibited by 80% of the 6-gingerol+6-shogaol combinations. Due to
the ginger matrix complexity and minute amount of biophenolics, the
researchers further investigated if increasing their individual amounts
in the ginger extract could cause an enhanced antiproliferative effect.
They observed that, specifically, ginger extract+6-gingerol and ginger
extract+10-gingerol in combination displayed remarkable synergistic
antiproliferative activity.
Furthermore, Hakim et al [71] showed that ginger extract (aqueous)
causes a greater inhibitory effect on the division of HCT 116 colorectal
cancer cells (IC50 = 3 mg/mL) as opposed to Gelam honey
(IC50 = 75 mg/mL). Interestingly, the collective action of the two nat-
ural agents (3 mg/mL ginger+75 mg/mL Gelam honey) synergistically
reduced the IC50 of Gelam honey (22 mg/mL). Extract of ginger was
also found to enhance the apoptosis effect of 5-fluorouracil.
Additionally, combination of γ-Tocotrienol and 6-gingerol sy-
nergistically induced cytotoxicity and apoptosis in HT-29 and SW837
colorectal cancer cells, corresponding to IC50 values of 105 and 70 μg/
mL, respectively. Additional benefits were a rise in apoptosis after 24 h
of treatment (21.2% and 55.4% in HT-29 and SW837, respectively)
with unaffected normal hepatic cells and morphological changes such
as cell shrinkage and pyknosis [72]. Combination of 6-gingerol (45 μM)
with paclitaxel (0.36 μM) was able to reduce 83.2% growth of HeLa
cells, which was more effective compared to 6- gingerol (45 μM) with 5-
FU (22.5 μM) (52% inhibition) or 6-gingerol treatment alone (10.75%
inhibition) [23]. In addition, combined treatment of zingerone and its
novel derivative synergistically suppressed hepatocellular carcinoma
metastasis by the inhibition of the TGF-β1 induced epithelial-me-
senchymal transition and suppressed migration and invasion of hepa-
tocellular [73].
Rahman et al [74] studied the anticancer properties of a number of
compounds including 6-gingerol, epigallocatechin gallate (EGCG),
asiaticoside (AS) and vitamin E (tocotrienol-rich fraction (TRF)). EGCG
M.F. Mahomoodally, et al.
+ 6-gingerol synergistically induced apoptosis and inhibited the
growth of 1321N1 and LN18 glioma cancer cells. On the other hand, all
tested combinations (TRF + 6-gingerol, TRF + EGCG and EGCG + 6-
gingerol) were reported to be antagonistic on SW1783. Moreover, Ko-
towski et al [75] found that although 6‐shogaol combined with cisplatin
displayed an antagonistic effect, when coupled with irradiation ex-
hibited a synergistic decrease of clonogenic survival in head and neck
squamous cell carcinoma cell lines.
Moreover, gingerol synergised cytotoxicity of doxorubicin on liver
cancer cells without influencing the cellular pharmacokinetics. Also,
gingerol decreased the IC50 of doxorubicin against HepG2 and Huh7
liver by 10- and 4-fold, respectively. On top of that, treatment with only
doxorubicin induced cell growth at S-phase and G2/M-phase, while its
blending with gingerol arrested cell cycle at the G2/M-phase. In addi-
tion, co-incubation with 6-gingerol (30 μM) caused a complete blockage
of the exaggerated vasoconstriction and impaired vascular relaxation
caused by doxorubicin [76]. In addition, ElAshmawy et al [77] reported
that co-treatment of ginger extract (100 mg/kg orally day after day)
alongside doxorubicin (4 mg/kg i.p. for 4 cycles every 5 days), ad-
ministered to mice starting on the 12th day of inoculation of Ehrlich
ascites carcinoma cells, markedly amplified survival rate, reduced
tumor volume, raised the level of phosphorylated AMPK (PAMPK), and
improved related pathways in mice compared to doxorubicin group.
Moreover, histopathological findings showed improved apoptosis and
absence of multinucleated cells in tumor tissue of the ginger ex-
tract + doxorubicin group.
A number of clinical trials also proved that supplementation of
ginger helps to decrease the severity of acute chemotherapy-induced
nausea in cancer patients [78–81]. Nausea and vomiting are among the
most common and troubling adverse effects associated with che-
motherapy [79]. Nevertheless, one of the likely side effect of radio-
therapy to the neck and head area is xerostomia, which is a subjective
feeling of dry mouth accompanied by decreased salivation. Shooriabi
et al [82] observed that ginger can improve the xerostomia symptoms
by increasing the rate of salivary secretion in patients undergoing
radiotherapy. Nevertheless, Chamani et al [83], reported that ginger
decreased the severity of dry mouth in patients with post-radiation
xerostomia but did not improve dry mouth symptoms or the patients’
quality of life.
6. Nanotherapeutic application
The emerging field of nanomedicine has the ability to change the
way cancer therapy is being provided [84,85]. By targeting the vascular
tissue and cellular characteristics exclusive to cancer cells [86], nano-
medicine ensures that the drugs are delivered at the right sites, there-
fore making drug delivery and absorption more successful [87,88].
Even though the potential of nanotechnology in the treatment/man-
agement of cancer is a recent and novel development [89,90], sig-
nificant research has been done in the area in order to optimize its
mechanism [91], pharmacokinetics [92] and delivery [93] as well as
the searches for new nano-composites such as graphene [94,95] or
hybrid polymer-metal composites for drug delivery [96]. Nanomedicine
reduces the chances of developing cancer cells that are resistant [97],
and more importantly, it may allow for more than one type of cancer to
be targeted during one treatment [98].
The benefits and therapeutic applications of liposomal based drug
delivery have been reviewed [99,100] and while a vast number of ap-
plications are in colon cancer, its significance in oral cancer therapy is
also discussed [101]. In particular, the work carried out by Khalili et al
[102] found that PEGylated nanoliposomal formulation of gingerol
increased its cytotoxic effect against breast cancer MCF-7 cell at a re-
duced concentration, allowing a slower drug release, when compared
with liposomal and standard gingerol. PEGylation allowed a controlled
drug release and protect the liposome against the immune system and
lipase enzymes which cause lipid solvation, thereby enabling a longer
7
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
blood circulation system and enough time to reach the target tumor
cell. Similarly, Behroozeh et al [103] observed that PEGylated nano-
niosomal gingerol showed higher cytotoxicity on T47D breast cancer
cell than the standard drug. More than 76% of the gingerol drug were
enclosed in the PEGylated nanoniosomal formulation and the gingerol
release from the nanoparticles consisted of an instant and fast release
phase at the start and then a slower release phase. Applications have
also been carried out in the treatment of lung cancer [104].
6-shogaol enriched liposomes in a DMPG-Na carrier also showed
enhanced in vitro and in vivo anticancer action. The release of 6-shogaol
from the liposomes was slower than that from ginger oleoresin at all the
tested pH ranges, which showed reduced outcome on the dissolution of
6-shogaol from the inner core compartment of the liposomes. In addi-
tion, the 6-shogaol rich ginger oleoresin loaded liposomes showed
better cytotoxic effect than the 6-shogaol rich ginger oleoresin and the
blank liposomes, which can be justified to a greater cellular uptake of
liposomes through phagocytosis or the fusion process of lipid lipo-
somes. Moreover, the 6-shogaol rich ginger oleoresin loaded liposomes,
(100, 200 and 400 mg/kg body weight) caused an increase in life span
in mice with Dalton’s Ascitic Lymphoma up to 91.5%, 92.5% and
93.5%, respectively, as opposed to the batch challenged with only the
6-shogaol rich ginger oleoresin (78%, 81% and 84%, respectively)
[105].
Additionally, Zhang et al [106] showed the specificity of nano-
particles, functionalized with ginger bioactives, to colon cancer cells
and the stability and non-toxicity of the ingested nanoparticles in so-
lutions similar to the stomach and intestine matrices and conditions.
Mouse colitis models showed that the nanoparticles were mainly ab-
sorbed in the intestinal epithelial cells and macrophages and were ef-
fective in preventing colitis associated cancer. Both tumor numbers per
mouse and tumor loads were significantly decreased by the ginger de-
rived nanoparticles treatment of azoxymethane/dextran sodium sulfate
colitis-associated cancer-induced mice. In addition, the level of pro-
inflammatory cytokine and cyclin D1 mRNA were also decreased,
suggesting that a reduction in cell proliferation during colitis-associated
cancer development.
Zhang et al [107] further reconstructed the lipid groups of ginger
functionalized nanoparticles to ginger-derived nanovectors (GDNVs) to
behave as a delivery platform for doxorubicin in the treatment of colon
cancer. Comparable to the previously functionalized ginger nano-
particles, the GDNVs were proven to be non-toxic and absorbed by
cancer cells in the large intestines and more importantly the GDNVs
have the capacity to encapsulate doxorubicin (95.9% at a ginger lipid
concentration of 100 μmol/L), and displayed a better pH-dependent
drug-release profile compared to commercially available liposomal-
doxorubicin. On top of that, the doxorubicin-GDNVs were very stable at
4 °C (up to 25 days), retained their ability to load doxorubicin, and
exhibited a time-dependent release profile which decreased the release
of doxorubicin from GDNVs and resulted to a sustained cytotoxic effect
against colon cancer cells.
The researchers then generated nanoparticles with a high affinity to
Colon-26 tumors in vivo by modifying the ginger-derived nanoparticles
to incorporate folic acid, a molecule showing high affinity for folate
receptors. These receptors are highly expressed on many types of tu-
mors, while being almost undetectable on healthy cells. The authors
demonstrated that the folic acid nanovectors efficiently loaded and
delivered doxorubicin into cancer cells and inhibited tumor growth.
7. Conclusion
The current review showcases the cytotoxicity propensities of ginger
and its main bioactive compounds to a number of cancer types with
particular attention on breast, cervical, colorectal, leukemia, liver, lung,
nasopharyngeal, ovarian, prostate, and retinoblastoma types. Further
evidence is presented to show that apoptotic mechanisms are depen-
dent on cancer type. Ginger and its active compounds also exerted
M.F. Mahomoodally, et al.
inhibitory effect against key enzymes linked to cancer progression in-
cluding cytochrome 450, cyclooxygenase-2, matrix metalloproteinase-2
and -9, telomerase, and leukotriene A4 hydrolase. In addition, an en-
hancement in the efficacy of chemotherapeutic drugs and reduction of
the side effects of radiotherapy was exhibited by ginger. More inter-
estingly however, future work remains to be done to provide a com-
prehensive understanding of the interactions of the bioactive phyto-
chemicals in ginger in the human body system through in-vivo
preclinical trials. Also, the application of nanotechnology seems to be a
better delivery system for ginger compounds. Nonetheless, further
pharmacodynamic and pharmacokinetic studies to determine the mo-
lecular pathway exhibited by these nano-formulations and their bioa-
vailability are needed. Last but not least, since ginger is traditionally
used against cancer, there is a need for more human clinical trials to
validate the exact dose and mode of administration as practiced tradi-
tionally to establish its efficacy and observe any possible adverse re-
actions.
Funding support
No specific funding was disclosed.
Declaration of Competing Interest
The authors made no disclosures.
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